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WO2001096319A1 - Processus de trans-glycosidation pour la synthese de (2r, 2-alpha-r, 3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-1,4-oxazine - Google Patents

Processus de trans-glycosidation pour la synthese de (2r, 2-alpha-r, 3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-1,4-oxazine Download PDF

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Publication number
WO2001096319A1
WO2001096319A1 PCT/US2001/018242 US0118242W WO0196319A1 WO 2001096319 A1 WO2001096319 A1 WO 2001096319A1 US 0118242 W US0118242 W US 0118242W WO 0196319 A1 WO0196319 A1 WO 0196319A1
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Prior art keywords
palladium
compound
formula
hydrogenation
carbon
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PCT/US2001/018242
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English (en)
Inventor
James M. Mcnamara
Matthew M. Zhao
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Merck and Co Inc
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Merck and Co Inc
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Publication date
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Priority to AU2001269749A priority Critical patent/AU2001269749A1/en
Publication of WO2001096319A1 publication Critical patent/WO2001096319A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to processes for the preparation of (2R, 2- alpha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-l,4- oxazine which is useful as an intermediate in the preparation of certain therapeutic agents.
  • the present invention provides a process for the preparation of (2R, 2-al ⁇ ha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl) ⁇ henyl]ethoxy-3-(4-fluorophenyl)- 1,4-oxazine which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
  • (2R, 2-alpha-R, 3a)-2-[l-[3,5-bis(trifluoro- methyl)phenyl]ethoxy-3-(4-fluorophenyl)- 1,4-oxazine is an important intermediate for a particularly useful class of therapeutic agents.
  • there is a need for the development of a process for the preparation of (2R, 2-alpha-R, 3a)-2-[l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-l,4-oxazine which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
  • the subject invention provides a process for the preparation of (2R, 2-alpha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)- 1,4-oxazine via a very simple, short, relatively inexpensive and highly efficient synthesis.
  • novel process of this invention involves the synthesis of (2R, 2- alpha-R, 3a)-2- [ 1 -[3 ,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)- 1 ,4- oxazine.
  • present invention is concerned with novel processes for the preparation of a compound of the formula:
  • This compound is an intermediate in the synthesis of compounds which possess pharmacological activity.
  • such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of psychiatric disorders, inflammatory diseases, and emesis.
  • the present invention is directed to processes for the preparation of (2R, 2-al ⁇ ha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl) ⁇ henyl]ethoxy-3-(4-fluorophenyl)- 1,4-oxazine of the formula:
  • An embodiment of the general process for the preparation of (2R, 2- alpha-R, 3 a)-2- [ 1 - [3 ,5-bis (trifluoromethyl)phenyl] ethoxy-3 -(4-fluorophenyl)- 1 ,4- oxazine of the formula: comprises:
  • the reducing agent is a hydride reducing agent known in the art and it is more preferred that the reducing agent is di(iso- butyl)aluminum hydride (DIBAL).
  • Preferred solvents for Step (1) comprise an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran, toluene and mixtures thereof are the more preferred organic solvents.
  • the reaction is between about -70 and 25°C, and preferably about -20°C.
  • Step (2) it is preferred that activation of the 2-hydroxy group is conducted via reaction with trichloroacetonitrile to provide the corresponding trichloroimidate (-CNCI3), or alternatively a halogenating agent to provide derivatives substituted with F, Cl, Br, or I, or an optionally substituted alkyl or aryl acid chloride or acid anhydride to provide the corresponding optionally substituted ester (-O-CO-R or -O-COCF3 or -O-COCCI3 wherein R is Cl -6alkyl, substituted Ci -6alkyl, phenyl or substituted phenyl) .
  • Preferred activating conditions employ trichloroacetonitrile and a weak base such as potassium carbonate in an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran, toluene and mixtures thereof are the more preferred organic solvents.
  • Activation is typically carried out at room temperature.
  • the Lewis acid is selected from boron trifluoride etherate, TMSOTf, titanium tetrachloride, tin tetrachloride, and the like.
  • the solvent is typically an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran is the more preferred organic solvents
  • THF tetrahydrofuran
  • diethyl ether diethyl ether
  • diglyme diglyme
  • methyl t-butyl ether and mixtures thereof, wherein tetrahydrofuran is the more preferred organic solvents
  • the reaction is typically carried out at a temperature range of between about -50 and about 50 °C.
  • the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman' s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon.
  • the product from Step (3) is contacted with a strong inorganic or organic acid prior to conducting the hydrogenation.
  • the acid is selected from hydrochloric, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, tartaric acid, citric acid, malic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, trifluoromethane- sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid and 4- toluenesulfonic acid, wherein the most preferred acids are hydrochloric acid, hydrobromic acid or 4-toluenesulfonic acid.
  • the solvent for the hydrogenation comprises a solvent which is selected from the group of C ⁇ -C 4 primary, secondary and tertiary alcohols, and water.
  • Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise methanol and mixtures of methanol and water.
  • the temperature of the reaction mixture for the hydrogenation is from about 10°C to about 50°C, wherein the most preferred temperature is about 20-25 °C.
  • the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
  • Step (5) the dehydrogenation is conducted under dehydrogenating conditions such as dibromouricil (DBU) and N-chlorosuccinimide.
  • the solvent typically comprises a polar aprotic solvent, such as selected from acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like.
  • a preferred solvent is dimethylformamide.
  • the reaction is typically carried out at a temperature range of between about -50 and about 50 °C and preferably about 0 °C.
  • the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman' s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C ⁇ -C primary, secondary and tertiary alcohols, and water.
  • the solvent may also comprise a polar aprotic solvent selected from acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like (such as may be present from the previous Step (5).
  • Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise methanol and mixtures of methanol and water.
  • the temperature of the reaction mixture for the hydrogenation is from about 10°C to about 50°C, wherein the most preferred temperature is about 20-25 °C.
  • the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
  • An embodiment of the present invention concerns a process for the preparation of (2R, 2-alpha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)- 1,4-oxazine of the formula:
  • the hydrogenation is catalytic hydrogenation.
  • the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman' s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon.
  • the solvent for the hydrogenation comprises a solvent which is selected from the group of C ⁇ -C primary, secondary and tertiary alcohols, and water.
  • Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise ethanol or methanol and mixtures thereof with water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10°C to about 50°C, wherein the most preferred temperature is about 20-25 °C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
  • the (2R, 2-alpha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl)phenyl]ethoxy- 3 -(4-fluorophenyl)- 1,4-oxazine obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
  • Crystalline 4-benzyl-2-hydroxy-l,4- oxazin-3-one was filtered, washed with water and then dried in a vacuum oven at about 60 °C under a stream of N 2 (72-76% yield); m.p. 134 °C.
  • the pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50% NaOH.
  • MTBE 300 mL was added, the layers were separated and the aqueous layer was further extracted with MTBE (3 x 150 mL).
  • the organic layers were combined and concentrated in vacuo (bath at 30-35 °C; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82% yield) with a boiling point of 187- 189 °C.
  • the combined organic layers were washed with brine (5 L) and l,4-diazabicyclo[2.2.2]- octane (240 g) was added.
  • the solution was concentrated to approximateky 4 mL/g of alcohol (KF ⁇ 200 ⁇ g mL; 2-propanol ⁇ 5 vol%).
  • the mixture was seeded at 40 °C, allowed to cool to RT to from a seedbed and then cooled to 0 °C.
  • the crystalline product was filtered, washed with cold heptane and dried to provide the DAB CO complex (70% yield; e.e.>99%).
  • the combined organic layers were washed with brine and l,4-diazabicyclo[2.2.2]octane (740 g) was added.
  • the solution was concentrated to approximateky 4 mlJg of alcohol (KF ⁇ 200 ⁇ g/mL; 2-propanol ⁇ 5 vol%).
  • the mixture was seeded at 40 °C, allowed to cool to RT to from a seedbed and then cooled to 0 °C.
  • the crystalline product was filtered, washed with cold heptane and dried to provide the DABCO complex (75-80% yield; e.e.>99%).
  • the organic extract was washed with water (2 x 41 ml) and dried by azeotropic distillation.
  • a solution of HC1 gas in isopropyl acetate (10%w/v, 36.5 ml) was added, followed by water (0.36 g), followed by a solution of HC1 gas in isopropyl acetate (10%w/v, 36.5 ml).
  • the mixture was stirred for 3 days then filtered to isolate the title compound (11.7 g) (??% recovery from crude free base) 97.6% d.e. by HPLC.
  • N-((S)- -methylbenzyl)-4-fluorophenylglycine (1.4 kg), diisopropylethylamine (1.99 1, 2.2 eq.) and 1,2-dibromoethane (3.78 1, 8.5 eq.) were combined in dimethylformamide (24.5 1) and heated at 125°C for 8 hours. The mixture was concentrated in a vacuum and partitioned between isopropyl acetate (15 1) and water (15 1). The organics were washed with water (15 1) and evaporated to give the crude oxazinone as a dark-coloured oil (1.44 kg).
  • the organic layer was separated, concentrated to a total volume of approximately 3 L and then flushed with ethanol (2x3 L) in vacuo (40-50 °C, 60 mmHg) at constant volume. Additional ethanol was added to dilute the mixture to a total volume of 8 L. The mixture was heated to 50 °C to effect complete dissolution of the crystals. Water (2 L) was added slowly over 2 h. The mixture was allowed to cool to ambient temperature and aged for 2 h. The solids were filtered, washed with a 3/1 mixture of ethanol/water (2 L) and dried to yield 1.85 kg of the traz-.s-glycoside (80% overall yield from the oxazinone).
  • Ethanol (2.5 L) and 5% Pd/C (50 g) were added to the crude imine solution.
  • the mixture was hydrogenated at 40 psi of hydrogen and ambient temperature for 2 h and then filtered over Solka-Floc to remove the catalyst.
  • the filter bed was washed with toluene (3 L) and 4-toluenesulfonic acid monohydrate (455 g) was added to the filtrates.
  • the mixture was partially concentrated to a total volume of approximately 6 L under a slight vacuum at 60-80 °C. After seeding and slow cooling to ambient temperature heptane (2 L) was added.
  • reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above.
  • specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un nouveau processus de préparation de 2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluorométhyl)phényl]éthoxy-3-(4-fluorophéenyl)-1,4-oxazine. Ce composé convient comme intermédiaire dans la synthèse de composés à activité pharmacologique.
PCT/US2001/018242 2000-06-09 2001-06-05 Processus de trans-glycosidation pour la synthese de (2r, 2-alpha-r, 3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-1,4-oxazine Ceased WO2001096319A1 (fr)

Priority Applications (1)

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AU2001269749A AU2001269749A1 (en) 2000-06-09 2001-06-05 Trans-glycosidation process for the synthesis of (2r, 2-alpha-r, 3a)-2-(1-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(4-fluorophenyl)-1,4-oxazine

Applications Claiming Priority (2)

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US21050000P 2000-06-09 2000-06-09
US60/210,500 2000-06-09

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011514892A (ja) * 2008-02-26 2011-05-12 サンド・アクチエンゲゼルシヤフト モルホリン誘導体の調製
CN102675240A (zh) * 2012-04-13 2012-09-19 浙江海正药业股份有限公司 4-取代基-2-羟基吗啉-3-酮及其制备方法
WO2012146692A1 (fr) 2011-04-29 2012-11-01 Sandoz Ag Nouveaux intermédiaires pour la préparation d'aprépitant ou de fosaprépitant de pureté élevée
CN103193725A (zh) * 2013-04-12 2013-07-10 上海医药工业研究院 (2r,3r)-2-[(1r)-1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐的制法
CN103214426A (zh) * 2013-04-12 2013-07-24 上海开义医药化工有限公司 阿瑞匹坦吗啉关键中间体或其盐的制法

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US7985592B2 (en) * 2004-02-13 2011-07-26 Chevron Oronite Company Llc High throughput screening methods for lubricating oil compositions
US8133994B2 (en) * 2005-10-06 2012-03-13 Dr. Reddy's Laboratories Ltd. Preparation of aprepitant
WO2009116081A2 (fr) * 2008-03-03 2009-09-24 Msn Laboratories Limited Procédé amélioré de préparation daprépitant
CN113582982B (zh) * 2021-06-15 2023-06-16 山东罗欣药业集团股份有限公司 一种nk1受体拮抗剂的制备方法

Citations (1)

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US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists

Family Cites Families (1)

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SK283070B6 (sk) * 1993-12-29 2003-02-04 Merck Sharp & Dohme Limited Substituované morfolínové deriváty, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011514892A (ja) * 2008-02-26 2011-05-12 サンド・アクチエンゲゼルシヤフト モルホリン誘導体の調製
JP2014159435A (ja) * 2008-02-26 2014-09-04 Sandoz Ag モルホリン誘導体の調製
WO2012146692A1 (fr) 2011-04-29 2012-11-01 Sandoz Ag Nouveaux intermédiaires pour la préparation d'aprépitant ou de fosaprépitant de pureté élevée
CN102675240A (zh) * 2012-04-13 2012-09-19 浙江海正药业股份有限公司 4-取代基-2-羟基吗啉-3-酮及其制备方法
WO2013152741A1 (fr) * 2012-04-13 2013-10-17 浙江海正药业股份有限公司 2-hydroxymorpholine-3-one 4-substituée et son procédé de préparation
CN102675240B (zh) * 2012-04-13 2015-01-14 浙江海正药业股份有限公司 4-取代基-2-羟基吗啉-3-酮及其制备方法
US9676736B2 (en) 2012-04-13 2017-06-13 Zhejiang Hisun Pharmaceutical Co., Ltd. 4-substituent-2-hydroxylmorpholine-3-one and preparation method thereof
CN103193725A (zh) * 2013-04-12 2013-07-10 上海医药工业研究院 (2r,3r)-2-[(1r)-1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐的制法
CN103214426A (zh) * 2013-04-12 2013-07-24 上海开义医药化工有限公司 阿瑞匹坦吗啉关键中间体或其盐的制法

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US20020022725A1 (en) 2002-02-21
US6395898B1 (en) 2002-05-28

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